Anti-viral composition

ABSTRACT

The invention relates to zinc-containing antiviral compositions and methods of treating viral infections. More specifically, the invention provides compositions and methods useful for ameliorating the symptoms of individuals suffering from infection with a broad range of viruses. Examples of viruses against which the compounds of the invention are active include rhinoviruses, varicella zoster, immunodeficiency viruses, including HIV.

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/608,029, filed Jun. 30, 2000, which is incorporated hereinin its entirety by reference, including figures.

FIELD OF THE INVENTION

[0002] The invention relates to compositions for the treatment orprevention of viral infection. The invention also relates tocompositions for the treatment of tumors.

BACKGROUND

[0003] Illnesses resulting from viral infection remain as a majorproblem to be addressed by modem medicine. To date, there is no 100%effective treatment for infection with any known virus. Recently therehas been progress towards treatment of several viral diseases, but thesetreatments are largely directed at specific viruses or classes ofviruses. For example, protease inhibitors targeting the virally-encodedhuman immunodeficiency virus (HIV) protease have been effective againstsome strains of HIV, and have been responsible, when used in combinationwith other anti-viral agents, for a decline in HIV-related deaths in theUnited States. However, the protease inhibitors are specific forspecific viruses or classes of viruses, and are not useful for thetreatment of viruses outside of those classes. In addition, there isevidence that strains resistant to these new agents are evolving.

[0004] It is noted that the virus-specific agents currently being usedin developed countries are very expensive, being beyond the means of agreat number of infected individuals throughout the world. In addition,the dosage regimens are complex and demand careful attention byphysicians and the infected individuals.

[0005] Because viruses co-opt the host's own normal intracellularmetabolic processes for their reproductive needs, a major difficulty inthe design of antiviral agents is to make agents that target the viruswithout toxicity to the host organism.

[0006] There is a need in the art for antiviral agents that areeffective against a broad spectrum of viruses, relatively non-toxic,inexpensive to produce, and simple to administer.

[0007] Many of the same problems plaguing those attempting to developantiviral therapies are faced by those wishing to cure cancer.Transformed cancer cells share the same cellular metabolic processes asnon-transformed cells, differing primarily in a loss of normal growthcontrol. Therefore, it has been difficult to develop treatmentstrategies that are effective against tumor cells without significanttoxicity to non-tumor cells. There is a need in the art for effectiveanti-tumor therapies that minimize the toxicity to non-transformed cellsand tissues.

SUMMARY OF THE INVENTION

[0008] The invention relates to methods and compositions for treatingthe symptoms of viral infection and for reducing the size or cellularload of a tumor.

[0009] More specifically, the invention encompasses a compositioncomprising the chemical compounds of Structure Nos. 1-4 and analogsthereof with antiviral activity. The invention also encompasses acomposition consisting essentially of any one or a combination of thechemical compounds of Structure Nos. 1-4. The invention also encompassesa composition comprising at least 10%, 20%, 50%, 75%, 90%, 95% or 99% ofany one or a combination of structures 1-4 by weight. Structures 1 and 2are chiral, as are structures 3 and 4. A composition of the inventionmay have relative amounts of (Structures 1 and 2): (Structures 3 and 4)in proportions ranging from 1:100, 1:10, 1:1, 10:1, or even 100:1.

[0010] The invention also encompasses an antiviral compositioncomprising a mixture of zinc oxide, aspartic acid, and high fructosecorn syrup.

[0011] In one embodiment, the composition comprising a mixture of zincoxide, aspartic acid, and high fructose corn syrup comprises one massunit of zinc oxide, about 2.5 mass units of aspartic acid, and about64.5 mass units of high fructose corn syrup.

[0012] The invention further encompasses an antiviral compositionconsisting essentially of a mixture of zinc oxide, aspartic acid andhigh fructose corn syrup.

[0013] In a preferred embodiment, the high fructose corn syrup has thefollowing characteristics: a) about 77% solids and about 23% moisture;and b) a carbohydrate composition as follows: about 55% fructose; about41% dextrose; the remainder being higher saccharides. In anotherembodiment, pure fructose (i.e., a composition consisting essentially offructose), or a composition comprising about 96% fructose and 4% higherpolysaccharides, is used in the preparation of an antiviral compositionof the invention.

[0014] The invention further encompasses a method of making an antiviralor antitumor composition, such method comprising the steps of: a)combining zinc oxide, aspartic acid and high fructose corn syrup to forma mixture; b) heating the mixture until visible insoluble material isabsent; and c) dehydrating the resulting composition to less than orequal to 1.5% water.

[0015] In a preferred embodiment of the method, the step of heatingcomprises the sequential steps of: a) heating the mixture to 170° F. for10 minutes; b) heating the mixture to 180° F. for 15 minutes; and c)heating the mixture to 190° F. for 3 to 5 hours, until no insolublematerial is visible to the naked eye.

[0016] In a preferred embodiment of the method, the mixture of step (a)comprises one mass unit of zinc oxide, about 2.5 mass units of asparticacid, and about 64.5 mass units of high fructose corn syrup.

[0017] In a further preferred embodiment of the method, the highfructose corn syrup has the following characteristics: a) about 77%solids and 23% moisture; and b) a carbohydrate composition as follows:about 55% fructose, about 41% dextrose, with the remainder being highersaccharides.

[0018] The invention further encompasses a method of reducing theduration of symptoms of viral infection, the method comprising the stepof administering a therapeutically effective amount of a compositioncomprising a chemical compound selecting form the group consisting ofstructures 1-4 or an analog thereof having antiviral activity, such thatthe duration of the symptoms is reduced.

[0019] In a preferred embodiment, the virus is one which causes thecommon cold.

[0020] In another preferred embodiment, the virus is herpes zoster(varicella zoster).

[0021] The invention further encompasses a method of reducing the titerof a virus in a virally infected individual, the method comprising thestep of administering a therapeutically effective amount of acomposition comprising, selected from the group consisting of structure1-4 an analog thereof, such that the titer of the virus in theindividual is reduced.

[0022] The invention further encompasses a method of increasing thenumber of CD⁴⁺ T cells in an individual infected with humanimmunodeficiency virus, the method comprising the step of administeringa therapeutically effective amount of a composition selected from thegroup consisting of structure 1-4 an analog thereof, such that thenumber of CD⁴⁺ T cells is increased.

[0023] The invention further encompasses a method of maintaining thenumber of CD⁴⁺T cells in an individual infected with humanimmunodeficiency virus, the method comprising the step of administeringa therapeutically effective amount of a composition selected from thegroup consisting of structure 1-4 an analog thereof, such that thenumber of CD⁴⁺ T cells is maintained.

[0024] The invention further encompasses a method of reducing the sizeof a tumor in an individual, the method comprising the step ofadministering a therapeutically effective amount of a compositionselected from the group consisting of structure 1-4 an analog thereof,such that the size of the tumor is reduced.

[0025] In preferred embodiments of the methods of reducing the durationof symptoms of viral infection, reducing the titer of a virus,increasing or maintaining CD⁴⁺ T cells, or reducing the size or cellularload of a tumor, the composition is administered transmucosally.

[0026] In other preferred embodiments of the methods of reducing theduration of symptoms of viral infection, reducing the titer of a virus,increasing or maintaining CD⁴⁺ T cells, or reducing the size or cellularload of a tumor, the composition is administered parenterally.

[0027] The invention further encompasses a kit for performing themethods of reducing the duration of symptoms of viral infection,reducing the titer of a virus, increasing or maintaining CD⁴⁺ T cells,or reducing the size or cellular load of a tumor.

[0028] As used herein, the term “antiviral activity” refers to theability of a composition or treatment regimen to ameliorate the symptomsof a viral infection. Intiviral activity includes, but is not limited toan activity resulting in a reduction by at least 10% in viral titer or areduction by at least 10% in the severity or duration of the symptoms ofa viral infection. The symptoms of a viral infetion include not onlythose directly caused by viral replication and accompanying cell death,but also secondary symptoms, such as those caused by opportunisticbacterial infections that occur subsequent to the death of infectedcells.

[0029] As used herein, the term “analog” refers to a composition thatvaries from an original or primary composition by the presence of one ormore chemical additions, deletions or substititions not present in thestructure of the primary composition. An analog as used herein will haveat least 50% of the antiviral or antitumor activity of the primarycomposition, and preferably more, up to and exceeding 100% of theactivity of the primary composition. An analog may have physical orfunctional characteristics that differ from those of the primarycomposition, for example, different or enhanced solubility, membranepermeability, or biological half-life, while retaining anti-viral oranti-tumor activity. The term “analog” also refers to a differentenantiomeric form of a given compound, such as the dextrorotatory orlevorotatory form of a molecule or a compound made using one or anotherenantiomeric forms of a given constituent. As a non-limiting example,the compositions made by mixing the D, or L enantiomeric forms ofaspartic acid with zinc oxide and high fructose corn syrup as describedherein would be considered analogs of the composition made using themixed enantiomeric D+L form of aspartic acid.

[0030] As used herein, the term “high fructose corn syrup” refers to aliquid carbohydrate composition comprising at least 50% fructose byweight. The carbohydrate composition is preferably derived from corn orother vegetable or plant material. The remaining proportion may containvarious relative amounts of other saccharides, including, but notlimited to sucrose, dextrose and higher saccharides.

[0031] As used herein, the phrase “mixture comprising zinc oxide,aspartic acid, and high fructose corn syrup” means a combinationcomprising zinc oxide, the D, L, or D+L forms of aspartic acid, and highfructose corn syrup meeting the definition of high fructose corn syruppresented herein.

[0032] As used herein, the term “solids” refers to the matter presentafter the removal of water or solvent, such as by lyophilization orevaporation.

[0033] As used herein, the term “carbohydrate composition” refers to amixture consisting essentially of of higher and lower saccharides.Higher saccharides include those having more than two linkedcarbohydrate monomers or subunits, for example, trisaccharides (threemonomer subunits), tetrasaccharides (four monomer subunits) oroligosaccharides with more than four carbohydrate subunits. Lowersaccharides include those with one or two carbohydrate monomers. Acarbohydrate composition may initially be in the form of a solid orpowdered solid, or it may initially be in the form of a liquid solution.

[0034] As used herein, the term “visible insoluble material” refers toparticles of material in a solution that are visible to the naked eye,assuming natural or corrected 20/20 vision. A visible insoluble materialmay include particulate matter that settles near the bottom of acontainer holding a solution, or it may include fine particulate matterthat remains in suspension but reduces the transparency of the solution.A solution or mixture with no visible insoluble material may be colored,but will be transparent, with no visually observable cloudiness.

[0035] As used herein, the term “dehydrating” refers to a processwhereby water is removed from a solution or composition. According tothe invention, dehydrating may be accomplished by processes including,but not limited to, freeze-drying (lyophilization), dessication undervacuum with or without heating, or dessication at atmospheric pressurewith heating. A dehydrated composition of the invention will have about5% or less, preferably about 2.5%, 1.5%, 1%, 0.5%, 0.2%, 0.1% or less ofwater by weight.

[0036] As used herein, the term “reducing the duration of symptoms”means that the length of time symptoms of a viral infection are presentis lessened by at least 10% in a treated individual relative to anindividual receiving no treatment. The time or duration of symptoms of aviral infection is the time from which symptoms first become apparent tothe infected individual until such symptoms are not apparent to the sameindividual (i.e., symptoms are fully resolved).

[0037] As used herein, the term “administering” refers to a processwhereby a composition of the invention is introduced to the body of anindividual in need of treatment. Administration may, for example, be byway of absorption through oral or other (e.g., rectal or vaginal) mucosa(referred to herein as “transmucosal” delivery or administration.Alternatively, administration may be by intramuscular, intravenous orintraperitoneal delivery means, which are collectively referred toherein as “parenteral” administration or delivery. Topicaladministration, for example for the treatment of shingles, or otherviral infection affecting the skin, is not excluded from the meaning of“administering” presented herein.

[0038] As used herein, the term “therapeutically effective amount”refers to the amount of a composition of the invention necessary toreduce the symptoms of a viral infection by at least 10%, to slow orhalt the growth of a tumor, or to reduce the size of a tumor by at least10%.

[0039] A therapeutically effective amount may be delivered over a periodof days, weeks or longer in order to have the desired therapeuticeffect.

[0040] As used herein, the term “common cold” refers to the diseasesymptoms resulting from infection with members of the rhinovirus family.Symptoms can include any or all of sore throat, cough, nasal congestion,runny nose, sneezing, swollen glands, muscular achiness and fever.

[0041] As used herein, the term “reducing” or “reduced” when used torefer to the titer of a virus in an infected individual means that thetiter of virus is lessened by at least 10%, and preferably by 20%, 30%,50%, 70%, 90% or more, up to and including 100% (i.e., no detectablevirus present).

[0042] As used herein, the term “maintaining the number of CD⁴⁺ T” cellsrefers to the situation in which treatment according to the inventionresults in no fluctuation (increase or decrease by up to 5%) in thenumber of CD⁴⁺ T cells in a given volume of peripheral blood over aperiod of at least one week. Preferably, CD⁴⁺ T cell counts aremaintained for months or even years or decades following commencement oftreatment.

[0043] As used herein, the term “increasing the number of CD⁴⁺ T” cellsrefers to the situation in which treatment according to the inventionresults in an increase in the number of CD⁴⁺ T cells relative to thenumber of CD⁴⁺ T cells present prior to the commencement of treatment,with the increase being at least 5%, and preferably as much as 10%, 20%,30%, 50%, 75%, or even 100% or more, up to and surpassing 500 CD⁴⁺ Tcells per microliter of blood.

[0044] As used herein, the term “Human Immunodeficiency Virus” or “HIV”is meant to refer to all strains of human immunodeficiency viruses.Active human immunodeficiency virus infection results in a decline inthe number of CD⁴⁺ T cells, which in turn results in the incapacity ofthe infected individual to mount an effective immune response to viral,bacterial, fungal or parasitic infections.

[0045] As used herein, the term “reducing the size of a tumor in anindividual” means that the size of a solid tumor or the load of tumorcells from a non-solid malignancy (e.g., a leukemia) is decreased by atleast 10% or more, preferably as much as 20%, 30%, 50%, 70%, 90%, oreven up to and including 100% decreased (i.e., no tumor or tumor cells)relative to the tumor size or tumor cell number before treatmentaccording to the invention.

[0046] Further features and advantages of the invention will become morefully apparent in the following description of the embodiments anddrawings thereof, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047]FIG. 1 shows the chemical structures of the active compounds ofcomposition A (structures 1-4).

[0048]FIG. 2 shows the chemical structures of the active compounds ofcompositions B (structures 1 and 3).

[0049]FIG. 3 shows the chemical structures of the active compounds ofcompositions C (structures 2 and 4).

DESCRIPTION

[0050] The invention provides compositions and methods useful forameliorating the symptoms of individuals suffering from a viralinfection, for example, infection by viruses including rhinoviruses(i.e., common cold), varicella zoster, and HIV. The symptoms of otherviral infections treatable with the methods and compositions of theinvention include, but are not limited to those caused by infection withAdenoviruses, Poxviruses (including vaccinia viruses, and molluscumcontagiosum virus) Bunyaviruses (including Rift Valley fever virus,Sandfly fever virus, Dengue virus, and Punta Toro virus), Flaviviruses(including yellow fever virus and Japanese encephalitis virus),Herpesviruses (including cytomegalovirus (CMV), human herpesvirus-6,herpesviruses 1 and 2, and Epstein-Barr virus (EBV)), Paramyxoviruses(including respiratory syncytial virus (RSV), measles virus,parainfluenza viruses, and mumps), Orthomyxoviruses (including influenzaA, B and C), Hepadnaviruses (including hepatitis A, B, C, delta and Eviruses), Picomaviruses (including polioviruses, coxsackieviruses, andECHO viruses), Rhabdoviruses (including rabies virus), Togaviruses(including Venezuelan equine encephalitis virus), Filoviruses (includingEbola virus and Marburg virus), Papovaviruses (including human papillomaviruses), Rubiviruses (including rubella virus), Orbiviruses (includingColorado tick virus, Junin and Machupo viruses), Hantaan Viruses(including Hantaan hemorrhagic fever virus and Congo/Crimean hemorrhagicfever virus), and Retroviruses and Lentiviruses (including HTLV 1 and 2,and HIV 1 and 2).

[0051] The compositions of the invention may be used either alone, or incombination with other antiviral compounds. It is anticipated that theuse of the compositions of the invention in combination with otherantiviral compounds will be more effective than the use of eithercompound alone. The broad antiviral nature of the compositions of theinvention makes them well-suited for combination with antiviral drugshaving narrower spectra of activity, such as the anti-retroviral drugsAZT, ddI, ddC, the retroviarl protease inhibitors, or theanti-herpesvirus drugs acyclovir or gancyclovir. This type ofcombination therapy may be useful, for example, in limiting thedevelopment of resistance to the narrow spectrum drugs, as well assimply enhancing the efficacy of the narrow spectrum drugs.

[0052] The chemical structure of one embodiment of the invention isshown in FIG. 1. This composition is produced from the startingcomponents zinc oxide (ZnO), D+L aspartic acid, and high fructose cornsyrup as described below. Two additional compositions, comprisingStructures 2 and 3, respectively, are produced using the essentiallypure D or L forms of aspartic acid in place of the mixed enantiomer D+Lform and contain only the respective D or L enantiomeric forms of theresulting zinc-aspatate-sugar composition of the invention.

[0053] I. How to Make Compositions Useful for the Reduction of Symptomsof Viral Infection According to the Invention.

[0054] The primary components used to produce the anti-viralcompositions of the invention are zinc oxide, aspartic acid (D+L form oressentially enantiomerically pure D or L forms), and high fructose cornsyrup. Zinc oxide and mixed enantiomer aspartic acid are widelyavailable, as are essentially enantiomerically pure preparations of D orL aspartic acid.

[0055] High fructose corn syrup used in the production of the anti-viralcompositions is also widely available, although the exact compositionsof the various products vary depending upon the specific source. For usein the production of compositions according to the invention, highfructose corn syrup having approximately the following characteristicsis most preferred:

[0056] 1) 77% solids and 23% moisture

[0057] 2) Carbohydrate composition:

[0058] 55% Fructose

[0059] 41% Dextrose

[0060] 4% higher saccharides:

[0061] For example, 1.87% disaccharide (C₂₄H₄₄O22)

[0062] 1.49% trisaccharide (C₁₉H_(35.2)O_(17.6))

[0063] 0.37% quadsaccharide (C_(4.8)H_(8.8)O_(8.8)).

[0064] One commercially available high fructose corn syrup that issuited for use in producing the compositions of the invention isISOSWEET® 5500 (Staley; Decatur, Ill.). However, the invention is notintended to be limited to the use of this particular corn syrupformulation. In fact, not only may the proportions of each of thevarious components in the corn syrup preparation vary by about 20%(higher or lower than the proportions listed), essentially pure fructose(i.e., at least about 95% or more fructose) may be used as well.Similarly, other higher order sugars, dissolved in water, may be used,as long as the ZnO and aspartic acid components remain completelysoluble after the formulation is prepared in lozenge form. It is noted,however, that when pure dextrose was used to prepare a test composition,the resulting composition was not active in the amelioration orreduction of the symptoms of viral infection. Therefore, it is preferredthat fructose or higher order sugars be used in the preparation of thecompositions of the invention.

[0065] The following describes the steps one may take to make anti-viralComposition A according to the invention. This process results in thepreparation of mixed enantiomer (D+L) forms of the composition, i.e.,the composition including structures 1-4 presented in FIG. 1. The use ofessentially enantiomerically pure D or L forms (i.e., about 95% or moreof one enantiomer) in the same proportions of ingredients and the sameprocess steps will generate the Compositions B (L form of aspartic acidused, resulting in a composition including structures 1 and 3; see FIG.2) and C (D form of aspartic acid used, resulting in a compositionincluding structure 2 and 4; see FIG. 3).

[0066] Steps for the Preparation of Antiviral Composition A:

[0067] 1) Combine one part (by weight) zinc oxide, ZnO, with 2.5 partsD+L aspartic acid, 64.5 parts high fructose corn syrup as described,and, optionally, 5.5 parts distilled water; for example, combine 13.7 gof ZnO, 33.8 g D+L aspartic acid, 883.4 g Staley Isosweet® 5500, and,optionally, 75 g distilled water;

[0068] 2) Heat the combination with stirring for 10 minutes at 170° F.(mixture will be light yellow in color);

[0069] 3) Heat to 185° F. for 15 minutes;

[0070] 4) Heat to 190° F. for 3 to 5 hours (reaction is complete when noinsoluble material is visible to the eye and the color of thecomposition changes to dark brown);

[0071] 5) The composition is then dehydrated to less than or equal to1.5% H₂O, preferably about 1% or less, 0.75% or less, 0.5% or less, 0.3%or less, and most preferably about 0.2% water by weight by heating atabout 145° F. in a dehydrator. For the dehydration step, it ispreferred, although not absolutely necessary, that the composition beplaced on silicone release paper to facilitate the subsequent step offorming lozenges.

[0072] The proportions of each ingredient in the composition may bevaried (increased or decreased) by about 20% and still result in acomposition with some anti-viral or anti-tumor activity. That is, theformulation presented above represents the most effective combination ofingredients known, but varying the amounts of aspartic acid and/or zincoxide within about 20% of the stated proportions will produce an activecomposition, provided the solubility of the ingredients is maintained.Specifically, it is noted that increasing the proportion of zinc oxideresults, at least with the high fructose corn syrup and aspartic acidpreparations tried, in precipitation of solids as the composition isdehydrated, or in the failure to obtain complete solubilization in thefirst place. That is, while proportions of the ingredients may be variedover the stated ranges, it is preferred that there be no precipitationof solids during the preparation of the compostions.

[0073] Following dehydration, the composition is rolled or pressed intolozenges (generally, lozenges comprise about 1 gram of the composition,although larger or smaller lozenges may be made for particularapplications). Alternatively, the composition may be dissolved in asuitable carrier (e.g., buffered saline or other pharmaceuticallyacceptable solution) for injection or mixed with other suitablepharmaceutical carriers (e.g., surfactants, lubricants, etc.; see“Administration and Dosages”, below) for other routes of administration.

[0074] An example of how to make a preparation containing Composition Afor parenteral administration is as follows (the same steps are followedto prepare Compositions B and C for parenteral administration). 100grams of the dehydrated (about 0.2% water) Composition A prepared asdescribed above are dissolved in 1.5 liters of ultrapure water with USPNaCl to make an isotonic solution (i.e., about 2.8 grams). The finalcomposition is about 6.24% of the antiviral composition by weight. Twoparts of this preparation are mixed with one part of xylocaine (e.g., 2ml antiviral composition plus 1 ml xylocaine) immediately prior toadministration.

[0075] Analogs:

[0076] Analogs of the active constituents of antiviral Compositions A(Structures 1-4, shown in FIG. 1) include those variants that possessantiviral activity, that result from the use of essentiallyenantiomerically pure D or L aspartic acid in the preparation of thecomposition.

[0077] Other analogs of the compounds of Structures 1-4 include, but arenot limited to those with substituents on the carbohydrate(s), such asalkyl or aryl groups, which may, for example, enhance membranepermeability. Other analogs include those with charged or polarsubstituents (e.g., phosphate or phosphonyl or sulfate orsulfonyl-containing substituents) which may enhance water solubility. Itis understood that one skilled in the art of synthetic orgainc chemistrymay synthesize such analogs as desired from readily availableprecursors.

[0078] Essentially, any substituent may be added or changed, includingwholesale replacement of the fructose with other saccharides orsaccharide polymers, as long as the change does not dislpace the zincconstituent of the compound and the compound continues to have antiviralactivity as defined herein.

[0079] Methods of Assessing Viral Titer and the Antiviral Activity ofAnalogs of the Compounds of Structures 1-4

[0080] A plaque-formation assay to monitor viral titer involves theaddition of a known amount of serum from an infected individual to amonolayer culture of cells susceptible to infection by the virus beingtitered. If a particular virus being treated does not appear in theserum of infected individuals during the normal course of infection, theviral titer may be measured by swabbing the infected tissue with anabsorbent material and measuring the amount of virus removed on theswab. As used in this context, an individual may be a human or ananimal, including an experimental animal, such as a mouse, rat, rabbit,goat, etc. Following incubation for a period of time that will also varywith the cell type and virus, monolayers are either stained with a vitalstain (i.e., a stain, such as trypan blue that is differentially takenup or excluded by viable, versus non-viable cells), or fixed and stained(e.g., with Giemsa stain). In either case, staining serves to visualizeplaques caused by viral infection of cells of the monolayer. The numberof plaques arising with a given amount (or dilution) of serum orsolution prepared from a swab represents the titer of that virus in thatsample. Samples taken before, during, and after treatment withcompositions of the invention may be compared to titers taken fromsimilar infected, untreated individuals at similar times afterinfection. The titer is reduced if, at a given point followingtreatment, it is at least 10% less in a treated individual than in anuntreated individual, and preferably if the titer is lessened by 20%,30%, 50%, 70%, 90% or more, up to and including 100% (i.e., nodetectable virus present) lower than the titer in the untreatedindividual.

[0081] The following describes a more specific example of aplaque-formation viral titer assay, designed to measure the titer ofrespiratory syncytial virus (RSV) particles in infected African greenmonkeys. Monkeys are infected by administration of viral stocks byeither intratracheal catheter or by intranasal instillation. Throatswabs are taken daily and placed in 1.0 ml of tissue culture medium (forexample, Dulbecco's Minimal Essential Medium with 10% fetal bovine serumand antibiotics). Titrations are performed on the 1.0 ml sample ofmedium after expression of fluid from the swab, using serial ten-folddilutions of the sample. Each dilution is inoculated into duplicatewells of a 24 well plate containing monolayer cultures of BSC-40 cells.The titers are obtained by microscopic examination of the cultures forviral induced cytopathology (i.e., plaques). Samples to be titered mayalso be obtained through bronchoalveolar lavage; titer procedures areessentially the same as for throat swabs.

[0082] One approach to measuring viral titer by cell viability uses thevital indicator 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), which is reduced by viable cells. Reduction of MTTresults in a calorimetric change that may be monitored either visuallyor by spectrophotometry. Since only viable cells reduce MTT, comparisonsof the optical density of medium from infected versus non-infected cellsreflect the killing of cells by a virus. The MTT assay has been used tomeasure viral titers using both non-adherent (Pauwels et al., 1988, J.Virol. Meth. 20: 309) and adherent (Takeuchi et al., 1991, J. Virol.Meth. 33: 61) cells.

[0083] The MTT assay is also well suited for the assessment of theefficacy of antiviral compounds, as shown by both Pauwels et al. (1988,supra) and Takeuchi et al. (1991, supra), both of which references arehereby incorporated by reference. This methodology may therefore be usedto assess the antiviral activity of an analog of the compound of FIG.1A. Essentially, two separate identical cultures of virally infectedcells may be cultured in the presence of MTT, with one of the twocultures further containing an antiviral composition. Both cultures arethen spectrophotometrically monitored for reduction of MTT. A higherlevel of MTT reduction in the sample with the antiviral compoundindicates higher cell viability and therefore an effect of the antiviralcompound against the virus. A composition (e.g., an analog of thecompound having a structure shown in FIG. 1) is effective as anantiviral agent in this assay if the MTT reduction is increased by atleast 10% in an infected culture containing the composition, relative tothe MTT reduction detected in an infected culture without thecompostion. The concentration of an antiviral composition necessary toinhibit the cytopathic effect (as measured by MTT reduction) of a virusby 50% is termed the IC₅₀ for that composition. An analog identified ashaving antiviral activity in this type of assay may then be tested fortoxicity according to methods known in the art before ultimately beingtested in human trials for antiviral efficacy.

[0084] For any analysis of analog antiviral activity, it is assumed thattest results are either compared with results obtained using similaramounts of the compound of Structure 1 or that the compound of Structure1 (or the compound of Structure 1 in the form of composition A) istested in side-by-side assays with the analog.

[0085] Another method for monitoring the efficacy of an anitviralcomposition is to monitor the number of viral target cells present invivo before and after treatment with the composition. This type of assayis well suited for measurement of viruses such as HIV, which infects andkills CD⁴⁺ T lymphocytes normally present in the circulation. Thus, anincrease in CD⁴⁺ T cells in an individual infected with a virus thatkills CD⁴⁺ T cells, following treatment with an antiviral composition oranalog compound, indicates that the composition or analog compound iseffective against that virus.

[0086] II. How to Use the Antiviral Compositions of the Invention.

[0087] A. Dosage and Administration

[0088] The compositions of the invention may be administered in a numberof different ways. Preparations comprising compositions A-C may beadministered through oral (i.e., transmucosal), rectal, transdermal(i.e., topical), vaginal and parenteral (including sub-cutaneous,intramuscular and intravenous) routes. The choice of the particularroute will depend upon the nature and severity of the viral diseasebeing treated, and may be adjusted or altered by the administeringphysician to suit a particular patient's needs. Generally, more severeor advanced infection is treated with parenteral administration eitherwith or without additional transmucosal administrations.

[0089] A preferred route of administration is passage across the oralmucosa. In this format, one or more lozenges (e.g., comprisingComposition A) as described above are placed along the gumline andallowed to dissolve slowly, generally over 30 minutes to one hour. Thisroute of administration is simple, effective, and requires no sterileapparatus such as hypodermic needles, syringes or IV equipment. Dosagesmay be increased or decreased by simply increasing or decreasing thenumber of such lozenges administered, as needed. It is preferred,although not absolutely necessary, that oral transmucosal administrationshould be performed within approximately 30 minutes to one hourfollowing a meal, to reduce the risk of gastrointestinal upset.

[0090] For oral transmucosal drug delivery, dosage and frequency ofadministration will vary with the severity and nature of the viralinfection. Generally, however, the initial dose may be one lozenge,administered as above, three times daily, until the desired clinicaleffects (e.g., reduced disease symptoms, reduced viral titer, increasedCD4 levels, reduced tumor size, etc.) are achieved.

[0091] Another preferred route of administration is parenterally viainjection. A composition of the invention may be dissolved in a suitablepharmaceutical carrier solution (for example, sterile buffered saline orsterile, pyrogen-free water, as described above. It is specificallynoted that dissolving the compositions of the invention in dimethylsulfoxide (DMSO) results in inactivation of the compositions. Therefore,it is preferred that DMSO not be used for preparation of thecompositions for parenteral administration. While not wishing to bebound by any single theory, it is possible that the metal chelatingactivity of DMSO is responsible for the inactivation of thecompositions. Therefore, it is also preferred that the use of otherchelators, such as EDTA, be avoided in the preparation of solubilizedcompositions of the invention.

[0092] It is further preferred, although not absolutely necessary thatfor intramuscular injection in particular, and parenteral administrationin general, an anesthetic, such as xylocaine or lidocaine, be added tothe preparation in order to avoid local discomfort at the site of theinjection.

[0093] For parenteral administration, the dose and frequency ofadministration will vary with the particular viral disease beingtreated. Dosages may be increased or decreased by the administeringphysician as deemed medically necessary or advantageous to achieve thedesired therapeutic effect. As an example, the preparation describedabove for parenteral administration (2 parts of 6.24% anti-viralcomposition to 1 part anesthetic) may be administered once every twodays for six days (i.e., 3 doses). This dosage regimen was effective inincreasing the CD4+ T cell counts of a number of individuals with activeHIV (see examples, below).

[0094] The parenteral administration may be combined with transmucosaladministration if desired. For example, one dosing regimen found to beeffective consisted of injection twice per week for 5 weeks with theparenteral antiviral composition/anesthetic formulation described above,in addition to oral transmucosal delivery of about 1 gram of the lozengeform of the same antiviral composition every day, three times a dayafter meals over the same period.

[0095] B. Toxicity

[0096] There is no indication of local or systemic toxicity ofCompositions A-C of the invention in humans or in animals whenadministered in the dose and frequency ranges described above. Inaddition to the human trial data described below, Swiss-Webster miceinjected intraperitoneally twice daily for 8 days with 0.05 ml of theComposition A formulation described above or a 1:10 dilution of itshowed no signs of disease or death.

[0097] C. Monitoring the antiviral efficacy of the compositions of theinvention.

[0098] The therapeutic efficacy of the compositions of the invention maybe monitored in several ways. First, the symptoms of infectedindividuals may be monitored. It is acknowledged that the symptoms ofviral infections treatable with the compositions of the invention willvary with the specific virus, and to some extent, with the individualinfected. However, the average duration of symptoms for a given viralinfection in humans or in animals is known in the art. A reduction inthe duration of symptoms as compared with duration in cases not treatedwith a composition of the invention is evidence of an effect of thecomposition against the viral symptoms. According to the invention, theduration of symptoms is reduced if symptoms are fully resolved (i.e.,absent) at least 10% sooner in patients treated with a composition ofthe invention than in untreated patients infected with the same virus.

[0099] For treatment of the common cold (i.e., rhinovirus infection) acomposition according to the invention is administered to a patient inapproximately one gram doses by the oral transmucosal route, generallythree times a day, following meals, for a time sufficient to have atherapeutic effect. Symptoms of rhinovirus infection, includingcoughing, fever, nasal congestion or runny nose may be readilyquantitated and are useful for monitoring the effectiveness oftreatment. As used herein, symptoms of the common cold are consideredreduced or decreased if any one of coughing, sneezing, fever, or nasalcongestion/runny nose are reduced or decreased by at least about 10% ormore following administration of a composition of the inventionaccording to the dosing regimen described. Bouts of coughing, counted ascoughs per hour are decreased according to the invention if they arereduced in number by at least 10% following treatment, preferably by atleast 20%, 30%, 50%, 70%, 90% or more, up to and including 100% (i.e.,no coughs per hour), relative to coughing prior to administration of acomposition of the invention. The defining parameters for reducedsneezing are the same as those for reduced coughing.

[0100] Fever is reduced or decreased according to the invention if it isreduced by 0.5° F. or more, 1° F., 1.5° F., 2° F., 3° F., 4° F. or even5° F. or more, down to and including normal body temperature of 98.6° F.(37° C.), relative to temperature before treatment acording to theinvention.

[0101] Nasal congestion or runny nose is decreased if the number oftimes an infected individual blows their nose per hour decreases by atleast 10% or more, preferably by at least 20%, 30%, 50%, 70%, 90% ormore, up to and including 100% (i.e., no nasal congestion/runny nose).

[0102] Additional symptoms of the common cold include sore throat andswollen glands, both of which are difficult to quantitate, however it isclear to an individual whether their throat is sore or not, and swollenglands may be readily detected by palpation. These symptoms are also ofuse in monitoring the efficacy of treatment methods according to theinvention.

[0103] For the amelioration or reduction of the symptoms of shingles(varicella zoster virus infection), a composition according to theinvention is administered to a patient in approximately one gram dosesby the oral transmucosal route, generally three times a day, followingmeals, for a time sufficient to have a therapeutic effect. According tothe invention, the symptoms of shingles are considered reduced if thelesions are at least 10% smaller, preferably 20%, 30%, 50%, 70%, 90% orup to and including 100% smaller (i.e., no lesion) following treatment,relative to the size of lesions before treatment. Alternatively,shingles are considered reduced or ameliorated if the number of lesionsis at least 10% fewer, preferably 20%, 30%, 50%, 70%, 90% or even up toand including 100% fewer (i.e., no lesions) following treatment,relative to the number of lesions present before treatment.

[0104] For the treatment of HIV, especially for maintaining orincreasing the CD4+ T cell count in an individual infected with HIV, anantiviral preparation according to the invention is administered eitherparenterally or transmucosally or via both routes as described herein,and CD4+ T cells are quantitated according to standard methods known inthe art. The Centers for Disease Control has established the followinglevels of CD4+ T cells as indicative of the various stages of AcquiredImmune Deficiency Syndrome (AIDS) in those infected with HIV. A CD4+ Tcell count of 500 per microliter or more correlates with theasymptomatic stage of the disease. A CD4+ T cell count of 499-200 permicroliter is associated with early symptoms of the disease, and a countof less than 200 per microliter is associated with severeimmunosuppression. A count of 499 or fewer is referred to herein as“active disease”. Preferably, a treatment that maintains or increasesCD4+ T cell counts will keep an infected individual's CD4+ T cell countabove 200 per microliter or more, and more preferably above 500 permicroliter. The compositions of the invention are useful for bothmaintaining and increasing CD4+ T cell counts; the compositions may beadministered to healthy infected individuals to maintain counts, or theymay be administered to infected individuals with active disease in orderto increase counts.

[0105] According to the invention, an individual's CD4+ T cell count isconsidered to be maintained if it does not fluctuate (increase ordecrease by up to 5%) over a period of 1 week or more in an HIV⁺individual. According to the invention, an individual's CD4+ T cellcount is considered to be increased if the number of CD4+ T cellsincreases by 5% or more, preferably by 10%, 20%, 30%, 50%, 70%, 90%,100% or more, up to and preferably exceeding 500 CD4+ T cells permicroliter following administration of an antiviral composition of theinvention.

[0106] In addition to monitoring CD4+ T cell counts, the efficacy of thetreatment methods of the invention in HIV infected individuals may bemeasured by monitoring the titer of the virus itself. Methods ofmeasuring HIV viral titer are well known in the art. The monitoring ofclinical efficacy of the treatment of other viruses with the methods ofthe invention may also be performed by measurement of titers of thoseviruses in infected individuals. Methods of measuring viral titer areknown in the art. Some methods vary with the specific virus, sinceindividual viruses have differing host cell type specificities.Generally, however, viral titer may be measured by plaque-formationassays, or by cell viability assays. Viral titer, and thereby viraldisease, is considered to be reduced according to the invention if itdecreases by at least 10%, preferably by at least 20%, 30%, 50%, 70%,90% or more, up to and including 100%, or the lack of virus in theindividual following treatment with a composition of the invention.

[0107] Compositions according to the invention can also be useful in thetreatment of tumors. One broad class of tumors that the compositions ofthe invention are expected to be particularly active against is thevirus-related tumors. Viruses associated with tumor development include,but are not limited to the following: HIV (associated with B-celllymphomas, cervical lymphomas, Hodgkin's disease, T cell lymphomas andKaposi's sarcoma); Epstein-Barr virus (EBV, associated with Burkitt'slymphoma and other B cell lymphomas, Hodgkin's disease andnasopharyngeal carcinoma); Hepatitis B and C viruses (associated withhepatocellular carcinoma); Human Papillomavirus (associated withcervical carcinoma); and Human T Cell Leukemia virus-1 (HTLV-1,associated with T cell leukemias). It is noted herein that whileopportunistic infection is a leading ultimate cause of death in AIDSpatients, HIV-related tumors are responsible for a significant number ofHIV-related deaths. Evidence is presented in Example 5 that HIV-relatedtumors may be reduced in size using the compositions and methods of theinvention. This is in no way meant to exclude non-viral-related tumorsfrom those that may be treated with compositions or methods of theinvention.

[0108] Administration of a composition according to the invention byparenteral or transmucosal routes or both as described herein can haltthe growth of a tumor or reduce its size or the number of tumor cells(tumor cell load) in an individual. Tumor size may be measured in anumber of ways, including for example, external palpation, X-ray,ultrasound, magnetic resonance imaging or radiographic imaging usingtumor-marker specific imaging agents. For non-solid tumors, such aslymphomas or leukemias, the number of abnormal cells can be directlymeasured, for example in samples of the blood or bone marrow. Accordingto the invention, tumor growth or the proliferation of cancer cells isconsidered to be halted or stopped if the size of the tumor or thenumber of abnormal cells present in a sample does not increase over aperiod of one week or more, preferably 2 weeks or more, 1 month, 6months, one year or preferably 2 years or more following administrationof a composition according to the invention to an individual in need ofsuch treatment. Alternatively, the size of a tumor or the number oftumor cells is considered to be decreased according to the invention ifit is at least 10% less, preferably 20%, 30%, 50%, 70%, 90% or even upto and including 100% less (i.e., no tumor or tumor cells) than the sizeof the tumor or the number of cells present prior to commencement oftreatment.

EXAMPLE 1

[0109] Reduction of the Symptoms of the Common Cold

[0110] The composition made according to the methods described hereinusing D+L aspartic acid, ZnO and high fructose corn syrup (referred toherein as Composition A) was tested for efficacy in reducing orameliorating the symptoms of the common cold by administering it to 14different volunteer subjects in 23 different instances in which theyreoprted symptoms of the common cold. Their symptoms included sorethroat, congestion or runny nose, sneezing, cough, swollen glands, andlaryngitis. In each instance, the volunteers were given three doses ofComposition A over a period of 3 hours to one day. In each instance, thesubjects reported amelioration of symptoms, all stating that the coldsymptoms were gone completely in periods ranging from 2 hours toovernight. The individual results are presented below in Table 1. It isclear from these results that Composition A is effective in amelioratingthe symptoms of the common cold. TABLE 1 Results of Trials ofComposition A Against the Common Cold SORE CONGESTION SWOLLENCOMPOSITION “A” SUBJECT THROAT COUGH RUNNY NOSE SNEEZING GLANDSTREATMENT OUTCOME 1. X 3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 2. X X3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 3. X X X 3x/d, 1d NO SYMPTOMS W/IN2 HR TO O/N 4. X X X 3x/d, 2d NO SYMPTOMS W/IN 2 HR TO O/N 5. X 1x/d, 1dNO SYMPTOMS W/IN 2 HR TO O/N 6. X 2x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N7. X 1x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 8. X X 2x/d, 1d NO SYMPTOMSW/IN 2 HR TO O/N 9. X X 2x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 10. X X3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 11. X 2x/d, 1d NO SYMPTOMS W/IN 2HR TO O/N 12. X 1x/d, 2d NO SYMPTOMS W/IN 2 HR TO O/N 13. X 3x/d, 1d NOSYMPTOMS W/IN 2 HR TO O/N 14. X 3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N15. X X X 3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 16. X X X X 2x/d, 1d NOSYMPTOMS W/IN 2 HR TO O/N 17. X X 3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N18. X X 1x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 19. X X X 2x/d, 1d NOSYMPTOMS W/IN 2 HR TO O/N 20. X X X 2x/d, 1d NO SYMPTOMS W/IN 2 HR TOO/N 21. X 3x/d, 1d NO SYMPTOMS W/IN 2 HR TO O/N 22. X X 2x/d, 1d NOSYMPTOMS W/IN 2 HR TO O/N

EXAMPLE 2

[0111] Ameliorating The Symptoms Of Varicella Zoster Infection(Shingles)

[0112] Varicella zoster is the Herpes virus responsible for bothchickenpox and shingles. Following infection with the virus, most oftenin childhood, individuals develop chickenpox. In some cases, after theinitial infection, the virus may remain dormant in infected nerveganglia for years, and often for decades, before re-activating to causethe painful lesions commonly known as shingles. In order to test theeffectiveness of the antiviral compositions of the invention on thesymptoms of this viral illness, Composition A was administered to twodifferent patients, each of whom had two separate diagnosed attacks ofshingles on different occasions, for a total of four separate cases ofshingles. In each case, Composition A was administered in lozenge formfor transmucosal delivery, about 1 gram per lozenge, 3 times per dayafter meals by slowly dissolving the lozenge along the gumline. Within 3to 4 days of the initial treatment, in each case the patients reportedamelioration of the symptoms. Treatment was continued for 7 to 10 days,after which symptoms had completely ceased and the lesions had largelydisappeared. In one instance, the diagnosing physician, upon a follow-upexamination 10 days after the initial visit expressed amazement at thedegree of recovery.

EXAMPLE 3

[0113] Maintaining or Increasing CD4+ T Cells in Individuals Infectedwith HIV

[0114] In order to test the efficacy of the antiviral compositions ofthe invention on HIV infection, HIV-infected volunteers in theAIDS-stricken country of Haiti were given Composition A, via bothparenteral and transmucosal delivery routes as described herein below,and the general health and CD4+ T cell counts of the patients weremonitored.

[0115] A composition for intravenous administration was prepared asfollows. 100 grams of the dehydrated (about 0.2% water) Composition A,prepared as described herein above using the D+L forms of aspartic acid,were dissolved in 1.5 liters of ultrapure water with USP NaCl to make anisotonic solution (i.e., about 2.8 grams of NaCl). The final compositionis about 6.24% of the antiviral composition by weight. Two parts of thispreparation are mixed with one part of xylocaine (e.g., 2 ml antiviralcomposition plus 1 ml xylocaine) immediately prior to intravenousadministration. Dosage is generally 3 ccs per injection.

[0116] 1. A 50 year old male patient, designated JF, was HIV positiveand had a CD4 count of 240 (active disease) at the commencement oftreatment. The patient was given 3 ccs of the Composition A/xylocainemixture detailed above intramuscularly three times per week for threemonths. At the end of one month, the patient's CD4+ T cell count was240/μl, which increased to 546/μl by the end of two months, and 993/μlby the end of three months. The patient was still alive 5 years afterinitial treatment.

[0117] 2. A 31 year old female designated KA, was HIV positive and had aCD4+ T cell count of 640 at the commencement of treatment. She received3 ccs of Composition A by intramuscular injection three times per weekfor three months. After the first 44 days of treatment, her CD4 countwas 993 μl.

[0118] 3. A 31 year old female designated AMK, was HIV positive and hada CD4+ T cell count of 640 at the commencement of treatment. The initialtreatment was Composition A in lozenge form three times per daytransmucosally for seven months. After five months of this initialtreatment, her CD4+ T cell count was maintained at 640/μl, and at theend of the first seven months her CD4 count was 854/μl. At the end ofthe first seven months of treatment, the patient began receiving, inaddition to the continued transmucosal doses of Composition A, 3 ccs ofComposition A by intramuscular injection twice per week for the nextthree months. At the end of the first month on the combined IM andtransmucosal delivery, her CD4 count was 860/μl, and at the end of thethird month (ten months total treatment time), her CD4 count was 820/μl.

[0119] After 11 months of total treatment time, due to political unrest,it was impossible to maintain the supply of Composition A to the clinicin Haiti, and a period of five and one half months elapsed beforetreatment could be re-started. During the time without treatment, thepatient's CD4+ T cell count declined to 570/μl. Upon there-administration of Composition A by the transmucosal delivery routethree times per day, the patient's CD4+ T cell count increased to 860/μlover two months. In an additional two months, the patient's CD4 countwas 820. The patient was in apparently good health, with noopportunistic infections reported two months later, at which timetreatment was again discontinued. One year after this seconddiscontinuation of treatment, the patient's CD4 count was 640, and thepatient continued in good health.

[0120] It is apparent from the data obtained in this study thatComposition A can increase the CD4+ T cell count in an HIV-infectedindividual and maintain an increased level over a period of at least 22months. It significant, from the results of withdrawal andre-administration of the drug (due to circumstances beyond the controlof the clinicians involved), that the level of CD4+ T cell countsrepeatedly responds in a manner that correlates with the use of thedrug.

[0121] 4. An HIV positive patient, the 7 year old son of patient AMK,was treated with transmucosal Composition A for over a year. Thepatient's initial CD4 count was not known due to lack of availability ofassay reagents, but he had a recent history of varicella zosterinfection, an opportunistic infection common among HIV patients withactive disease. After approximately one year on Composition A, treatmentwas discontinued. Eight months later, his CD4 count was 622, and he wasin apparent good health, with no further opportunistic infections.

[0122] 5. An HIV positive 23 year old female, designated CM, was treatedfor over a year with Composition A delivered transmucosally three timesper day. The patient's CD4+ T cell count was 240 prior to thecommencement of treatment, and 550 after three months of continuedtreatment. One week after the commencement of treatment, the patientreported a sensation of fullness in the abdomen, at which time aphysical examination revealed a firm, fixed lump of approximately 7 cmin the left illiac fossa. No sonogram or X-ray was performed.Approximately two months after the commencement of treatment, the masshad regressed to about 3 cm, and after 9 months of treatment the masswas not detectable.

EXAMPLE 4

[0123] Reduction of the Symptoms of Feline Immunodeficiency Virus (FIV)

[0124] A ten year old stray cat testing positive for FIV was treated bya veterinarian with a composition of the invention to determine whetherthe composition was effective against this virus. The animal was FeLVnegative. One cc doses of Composition A prepared as in the previousexamples were injected once per day intravenously for 8 days, afterwhich the doses were switched to intramuscular injection for twenty-onedays. After this initial dose regimen, the animal tested weakly positivefor FIV using a combination FIV Ab/FeLV Ag test kit (Idexx Corp.,Portland, Me.). Dosages were increased to 4 cc IM for three days, thenintravenously for 15 days, after which the FIV test was positive.Treatment was reduced to 1 cc IV per day for one month, and wasdiscontinued because the animal was not eating. The animal's appetiteand demeanor improved within three days of the cessation of treatment.Treatment with 0.5 cc IV once a day was re-started 6 weeks later for aduration of one month, followed by a week without treatment before dailyIV doses of 1 cc for three weeks, after which treatment wasdiscontinued. The animal remained in visible good health for three moreyears after the treatments ceased. Thirty one months after the cessationof treatment, and again 9 months after that, complete blood counts didnot reveal the luekopenia indicative of active FIV, nor had there been ahistory of opportunistic infections that one would expect if the viruswere active. The animal was euthanized forty months after the cessationof treatment, due to a primary pulmonary adenocarcinoma. It is believed,since blood work never revealed the blood cell changes that areindicative of the disease, that the treatments with the composition ofthe invention were effective in preventing the active stages of FIVdisease.

EXAMPLE 5

[0125] Reduction in Tumor Size Following Treatment with a Composition ofthe Invention.

[0126] Composition A was administered at a dose of 1 gram via the oraltransmucosal route three times a day to an individual with a palpableabdominal mass of approximately 7 cm in size. The individual was beingtreated primarily for the symptoms of active AIDS. However, over thecourse of treatment for three months, the solid tumor mass regressed tothe point that it was no longer palpable.

[0127] Another HIV⁺ patient with a palpable tumor mass (about 2 cm) inher breast was treated 3 times daily with 1 gram oral transmucosal dosesof Composition A. Over the course of treatment for three months, thetumor mass regressed to the point where it was no longer palpable.

[0128] Another HIV⁺ patient with two lung tumors, one approximately 5cm×7.5 cm and another approximately 5 cm×2.5 cm, was treated 3 timesdaily with 1 gram oral transmucosal doses of Composition A. After threemonths of treatment, the tumors had both regressed or shrunken byapproximately 50%. Treatment in this and several other patients beingtreated for active HIV, with or without accompanying tumors, wasdiscontinued due to violent political unrest and an embargo of Haitithat made continued shipment of drugs and follow-up care impossible.

OTHER EMBODIMENTS

[0129] Other embodiments will be evident to those of skill in the art.It should be understood that the foregoing detailed description isprovided for clarity only and is merely exemplary. The spirit and scopeof the present invention are not limited to the above examples, but areencompassed by the following claims.

1. A composition comprising the chemical compound having a structureselected from the group consisting of structures 1-4.